Lymphangioleiomyomatosis (LAM) is a progressive multisystem disease of women in which smooth muscle-like LAM cells proliferate in the lungs with cystic destruction of the lung parenchyma, often leading to oxygen-dependency, lung transplantation, and/or death in young adulthood. Renal angiomyolipomas, which are benign tumors that can cause pain and life-threatening spontaneous hemorrhage, occur in ~60% of LAM patients. LAM is caused by inactivating mutations in the TSC2 gene, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and inhibition of autophagy. mTORC1 and autophagy regulate cellular metabolic homeostasis. TSC2-deficient cells compensate for this by reprogramming their cellular metabolism, thereby creating metabolic vulnerabilities that provide therapeutic opportunities with high specificity to the reprogrammed cell. How to target reprogrammed metabolic pathways in LAM is incompletely understood, representing a key knowledge gap. In recently published data, we discovered that TSC2-deficient cells are dependent on autophagy for survival, both in vitro and in vivo. In unpublished data, we found that TSC2-deficient cells have distinctive autophagy-dependent vulnerabilities in glutamine metabolism and in the pentose phosphate pathway. Our proof-of-concept data indicate that the metabolic vulnerabilities of TSC2-deficient cells can be selectively targeted using currently available agents without the utilization of mTORC1 inhibitors. Our central hypothesis that metabolically-targeted therapeutic strategies will have highly specific efficacy in pre-clinical models of LAM will be addressed in three specific aims: 1) to define the mechanisms through which the metabolism of LAM patient-derived cells is reprogrammed; 2) to determine the impact of metabolomic reprogramming on the proliferation and survival of LAM patient-derived cells; 3) to determine the in vivo impact of metabolic reprogramming in preclinical models of LAM. This project will have high clinical impact by facilitating the development of completely novel, paradigm-shifting therapeutic concepts for LAM. Our ultimate goal is to halt the progressive loss of lung function in women with LAM, using approaches that are highly effective and safe.